2-SUBSTITUTED -3a,4,5,6,7,7a-HEXAHYDRO-5a,6,7,8,9,9a-HEXAHYDRO-9 A-HYDROXYPYRIDO (2,1-b) BENZOTHIAZOLIUM HALIDES

ABSTRACT

Novel pharmacologically active compounds have been prepared of the formulas   WHEREIN R1 and R3 are selected from the group consisting of hydrogen and (lower)alkyl; R2 is selected from the group consisting of hydrogen, (lower)alkyl, nitro, halogen, (lower)alkoxy, hydroxy and WHEREIN R4 and R5 when not concatenated are independently selected from the group consisting of hydrogen and (lower)alkyl and when concatenated form a radical selected from the group consisting of piperazinyl, piperidinyl, pyrrolidinyl and morpholinyl; X is halogen.

United States Patent [1 1 3,694,449 Wei [451 Sept. 26, 1972 54] Z-SUBSTITUTED -3A,4,5,6,7,7A- 2 HEXAHYDRO-5A,6,7,8,9,9A- TQ S HEXAHYDRO-9 A-HYDROXYPYRIDO l e 2,143 BENZOTHIAZOLIUM HALIDES R g [72] inventor: Peter H. L. Wei, 430 Ridge Lane,

Springfield, Pa. 19064 iii l O 22 Filed: March 11, 1971 i 4 1 21 Appl. No.: 125,410 and /S s2 U.S.Cl 260/2 94.a B, 1

- 260/2472 B; mac/2412a, 260/268 BC, 260/293.57, 260/306], H 8? 6 260/3063 424/248 424/250 424/266 wherein R and R are selected from the group con- 424/267 424/270 sisting of hydrogen and (lower)alkyl; R, is selected [5 Cl. C0711 f h g p i i g f hyd g (l y [58] Field of Search ..260/294.8 B mgigggmhglgggqzlby?galkoxyihygmxyvang- [56] References Cited N OTHER PUBLICATIONS Elderfield, Heterocyclic Compounds, Volume 5, wherein R and R when not concatenated are Wiley Publishers, Pages 496- 499; (I957) pendently selected from the group consisting of hydrogen and (lower)alkyl and when concatenated Primary Examiner-Alan L. Rotman form a radical selected from the group consisting of Attorney-Andrew Katko, Joseph Martin Weigman, piperazinyl, piperidinyl, pyrrolidinyl and morpholinyl; Dwight J. Potter, Vito Victor Bellino and Robert Xis halogen. Wiser 3 Claims, No Drawings [57] ABSTRACT Novel pharmacologically active compounds have been prepared of the formulas and Z-SUBSTITUTED -3A,4,5,6,7,7A-HEXAHYDRO- A,6,7,8,9,9A-HEXAHYDRO-9 A- HYDROXYPYRIDO (2,1-B) BENZOTHIAZOLIUM HALIDES DESCRIPTION OF THE INVENTION This invention is concerned with the preparation of novel chemical compounds which are pharmacologically active as central nervous system depressants. They are useful as calming agents for mammals.

The compounds are of the formulas:

and

wherein R andRg, are hydrogen and (lower)alkyl; R is selected from the group consisting of hydrogen, (lower)alkyl, nitro, halogen, (lower)alkoxy, hydroxy wherein R and R when not concatenated are independently selectedfrom the group consisting of hydrogen and (lower-)alkyl and when. concatenated form. a radical selected from the group consisting of piperazinyl, piperidinyl; pyrrolidinyland morpholinyl; X is halogen.

The compounds of FORMULA I may be prepared according to the following reaction scheme:

X Q-osmm.

wherein R R and X are the same as hereinabove definedand R is lower alkyl.

The compounds are prepared by heating the reaction in an alcohol solution at a temperature of 80 to 100 for a period of 3 to 8 hours. The solvent is removed and the residue is triturated with ether and dimethoxyethane and the crude solid material which is collected can be recrystallized from ethanol.

Compounds of FORMULA ll may be prepared by acetic the following procedure:

Q; s H acid wherein X is the same as hereinabove defined and R is lower alkyl. TI-Ie reactants are allowed to react in glacial acetic acid at a temperature of from 80 to 100 for a period of 2 to 5 hours. Upon cooling, the solid is collected and washed with dimethoxyethane and ether. The crude material can be recrystallized from ethanol.

Compounds of Formula I and Formula II wherein R is hydrogen may be prepared by the hydrolysis of the corresponding ester. The preferred method of hydrolysis is to use a -50 percent mixture hydrohalic acid such as hydrobromic acid at a temperature of from to 80 for a period of 20 to 40 minutes. After the solvent is removed at reduced pressure, the residue may be triturated with a solvent, such as acetone and collected.

As used herein the term (lower)alkyl is used to include hydrocarbon radicals such as methyl, ethyl, n-

=0 lglaclel =0 5 propyl, i-propyl and n-butyl. The term halogen is used to include chlorine, bromine and iodine.

In the evaluation of the biological activity of the compounds of this invention, the in vivo effects were tested as follows: The compound was administered orally or intraperitoneally to three mice (14 to 24 grams) at each of the following doses: 400, I27, 40 and 12.7 milligrams per kilogram of host body weight (MPK). The animals were watched for a minimum of 2 hours during which time signs of general stimulation, (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration), autonomic activity (i.e., miosis, mydriasis, diarrhea) were noted.

The compounds of this invention induce central nervous system depressant effects at a dose of 127 to 400 MPK. Thus the compounds of the invention, have demonstrated utility as pharmacologically active compounds in experimental and comparative pharmacology and are of value in treatment of mammals, e.g., mice, rats, etc., who are responsive to treatment with central nervous system depressant agents. Specifically the compounds may be administered for the purpose of inducing a calming effect in mammals.

When the compounds of the invention are employed as described above, they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, calcium carbonate and the like. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be administered by parenteral injection, e.g., intramuscular injection. The injectable solution may contain other solutes such as sodium chloride or glucose in a sufficient quantity to render the solution isotonic.

The dosage of the pharmacological agents of the invention may vary with the route of administration and the particular compound chosen.

The following examples are not to be construed as limitations of the invention:

EXAMPLE 1 4-Carboxy-2-(p-dimethylaminophenyl)-3a,4,5 ,6,7 ,7ahexahydro-3a-hydroxy-3-methylbenzothiazolium bromide ethyl ester p-Dimethylamino-N-methylthiobenzamide was prepared following the procedure of Gaomaise and Chambers. [J. Med. Chem. 11, 1205-8 (1968)].

An alcoholic solution of 6-bromo-2-carbethoxycyclohexanone (4.9 g, 0.02 m) and p-dimethylamino- N-methylthiobenzamide (3.6 g, 0.02 m) was heated to reflux for hours. After removal of ethanol the residue was treated with ether. The residue upon standing solidified. The crude material after treatment with dimethoxy ethane weighed 5.0 g and melted at l75-8 C. Recrystallization from ethanol gave pure ethyl ester of 4-carboxy-2-(p-dimethylaminophenyl)-3 a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-methylbenzothiazolium bromide, mp. 1813 C.

Anal. Calcd for c,,H,,BrN,o,s: C, 51.46; H, 6.14:

Found: C, 51.26; H, 6.09; N, 6.30. IR(KBr): 3.4 p. (OH): 5.8 (ester CO); 6.25 (C=N). NMR (CDCl 8 7.3 (m, 4); 4.3 (q, 2, OCH 1.3 (t, 3, CH NCH 3.2 (s, 3); 3.7 (m).

EXAMPLE 2 9-Carboxy-5a,6,7,8,9,9a-hexahydro-9a-hydroxypyrido[ 2, l -b]benzothia-zolium bromide, ethyl ester An acetic acid (60 ml) solution of 6-bromo-2-carbethoxy-cyclohexanone (12.45 g. or 0.05 m) and 2- mercaptopyridine (5.55 g or 0.05 m) was heated on a steam bath for 3 /2 hours. Upon cooling the solid that separated was collected and washed with dimethoxyethane and ether. The crude material was recrystallized from ethanol. The pure ethyl ester of 9-carboxy- 5a,6,7,8 ,9,9a-hexahydro-9a-hydroxypyrido[2,1- b]benzothiazolium bromide weighed 14.9 g, (82% yield), mp 206-207.

Anal. Calcd for C,.,H NO S'Br: C, 46.67; H, 5.03;

Br, 22.18; N, 3.89; S, 8.90.

Found: C, 46.48; H, 4.97; Br, 22.07; N, 4.03; S,

IR spectrum (KBr) showed the presence of ester absorption at 5.8 p. and the absence of keto carbonyl at 6.0 11.. NMR spectrum (DMSO-d,;), 6 1.1 (t, J=7Hz) 4.1 (q, J=7Hz). Other aliphatic protons as complex multiplets absorbed at 1.8 to 2.2 and 3.a, the hydroxy proton was found at 6 4.8 was exchanged in D 0.

EXAMPLE 3 5a,6,7,8,9,9a-Hexahydro-9a-hydroxypyrido[ 2, l -b ]benzothiazolium bromide A 48% HBr (30 ml) solution of ethyl ester 9-carboxy-5a,6,7,8,9,9a-hexahydro-9a-hydroxypyrido[ 2, l b]benzothiazolium bromide (6.0 g) was heated on a steam bath. Gas evolution ceased at the end of the reaction period (3 hours). The solvent was removed in vacuo and the residue treated with benzene and the benzene was also removed. The residue was finally treated with acetone and the solid collected which weighed 4.4 g. Upon recrystallization from ethanol pure 5a,6,7,8,9,9a-hexahydro-Qa-hydroxypyrido[2,1- b]benzothiazolium bromide melted at 21 35 C.

Anal. Calcd for C H NOS'Br: C, 45.83; H, 4.90; Br,

Found: C, 45.66; H, 5.09; Br, 27.40; N, 4.98; S.

IR spectrum (KBr) showed the disappearance of carbonyl absorption. NMR (DMSO-d,,): 6 8.5 (m); 4.6 (t); complex multiplet 1.8 8.

By analogous methods the chloride and iodide salts may be obtained.

EXAMPLE 4 9Carboxy-5a,6,7,8,9,9a-hexahydro-9a-hydroxypyrido[ 2, l -b]benzothiazolium bromide A 48% HBr solution (40 ml) of 9-carboxy- 5a,6,7,8,9,9a-hexahydro-9a-hydroxypyrido[2,1-b ]benzothiazolium bromide ethyl ester, (5.0 g) was heated gently in a hot water bath for 30 minutes. The solvent was removed at reduced pressure and the solid residue (3.0 g) after treatment with acetone was collected, and dried in a drying pistol at reduced pressure to afford product, mp l5.

Anal. Calcd for C H NO S'Br: C, 43.38; H, 4.25;

Br, 24.05; N, 4.22; S, 9.65.

Found: C, 43.08; H, 4.46; Br. 23.77; N, 4.26; S,

IR (KBr) 3.5 ,u. (OH); 5.85 (carboxyl CO). NMR (DMSO-d,;) 0 8.5 (m); aliphatic, 1.9 (m).

By methods analogous to those employed in Example 1, the following compounds are prepared:

TABLE I 4-carboxy-2-(m-chlorophenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide, methyl ester 4-carboxy-2-(p-ethylphenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-n-propylbenzothiazolium mide, i-propyl ester 4-carboxy-Z-(p-hydroxyphenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-methylbenzothiazolium chloride, ethyl ester 4-carboxy-2-(p-methoxyphenyl)-3a,4,5,6,7,7a-hexahydro-3-hydroxy-3-ethylbenzothiazolium bromide,

bro-

' methyl ester TABLE II 4-carboxy-2-(p-nitrophenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3 -ethylbenzothiazolium bromide 4-carboxy-2-(p-toluene)-3a,4,5 ,6,7,7a-hexahydro- 3a-hydroxy-3-methylbenzothiazolium chloride 4-carboxy-2-(p-bromophenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-methylbenzothiazolium bromide 4-carboxy-2-(p-ethoxyphenyl)-3a,4,5 ,6,7,7a-hexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide 4-carboxy-2-(m-chlorophenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide 4-carboxy-2-(p-ethylphenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-n-propylbenzothiazolium mide 5 4-carboxy-2-(p-hydroxyphenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-methylbenzothiazolium chloride 4-carboxy-2-(p-methoxyphenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide 4-carboxy-2-[p-(4-morpholinyl)phenyl]- 10 3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-methylbenzothiazolium bromide 4-carboxy-2-[ p-( l-piperidinyl )phenyl 3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-methylbenzothiazolium chloride 4-carboxy-2-(p-aminophenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-S-ethylbenzothiazolium bromide 4-carboxy-2-phenyl-3a,4,5,6,7,7a-hexahydro-3a- E-8% xl-i 'lliiil ifiil i illlhigiillf 4a, 4,5,6,7,7a-hexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide 4-carboxy-2-[p-( l-piperazinyl)phenyl]- 321,4,5,6,7,7a-hexahydro-3a-hydroxy-3-hydroxy-3- ethylbenzothiazolium chloride 4-ca.rboxy-2-[p-( l-pyrrolidinyl)phenyl]- 3a,4,5,6,7,7a-hexahydro-3a-hydroxy-B-methylbenzothiazolium bromide I claim: 1. A compound selected from the group consisting of bro- (Y IL Yin e x i wherein R is selected from the group consisting of hydrogen and (lower)alkyl and X is halogen. 2. A compound as defined in claim 1 which is 9-carboxy-5a,6,7,8 ,9,9a-hexahydro-9a0hydroxypyrido[e2 l bIbenzothiazolium bromide, ethyl ester.

3. A compound as defined in claim 1 which is 9-carboxy-5a,6,7,8,9,9a-hexahydro-9a-hydroxypyrido[ 2, l b]benzothiazolium bromide. 

2. A compound as defined in claim 1 which is 9-carboxy-5a,6,7,8, 9,9a-hexahydro-9ahydroxypyrido(2,1-b) benzothiazolium bromide, ethyl ester.
 3. A compound as defined in claim 1 which is 9-carboxy-5a,6,7,8, 9,9a-hexahydro-9a-hydroxypyrido( 2,1-b) benzothiazolium bromide. 